Background: Lung cancer remains the number one cause of cancer related death worldwide. Immune modulating therapy have shown long lasting survival, however, they are only effective in about 20% of patients. Although PD-L1 expression predicts tumor response, it is not a robust predictor. Circulating tumor cells (CTCs) or tumor derived extracellular vesicles (tdEV) may be another tumor response predictor. CTCs have been associated with survival in NSCLC. Our hypothesis is that CTC or tdEV changes predict early tumor response and it is an early marker of treatment efficacy.

Methods: Patients with proven advanced NSCLC referred to our center for immunotherapy by PD-L1 or PD-1 antagonists were eligible for inclusion. CellSave tubes were drawn at start of therapy (T0) and after 4 weeks of treatment (T1). EpCAM expressing CTCs were detected by the CellSearch system. EpCAM expressing tdEV which are present in the blood during CTC enumeration, were counted in the images from the CellTracks Analyzer, which were analyzed with the open source program ACCEPT. Response to therapy was measured by the response evaluation criteria in solid tumors (RECIST) and according to clinical evaluation of the treating physician. Patients were divided in groups based on response to therapy and presence of CTCs. Cox regression analyses were used to study the association between CTCs and tdEVS with both OS and PFS.

Results: 114 patients have been included (104 T0 samples, 71 T1 samples, 52 both a T0 and T1 sample). 53 patients have progressive disease (PD), 24 stable disease (SD), 23 partial response (PR) and 2 a complete response; 12 could not be evaluated yet. CTCs were present in 33 T0 samples (32%), and 20 T1 samples (28%). When CTCs were present at T0, patients had no response to therapy in 83% of cases, while patients without CTCs had no response in 68% of cases. Patients with increased CTC counts at T1 responded in 9% of the cases, versus 33% in patients with decreased CTC counts. CTCs were significantly correlated to survival at both time points independently (T0, HR=1.06, p=0.042; T1, HR=1.04, p=0.009). Comparing patients with a decrease of CTCs with those with an increase, Cox regressions showed a HR of 8.9 (p=0.041), while using the difference of CTCs between T1 and T0 as a continuous variable in the cox regression gave a HR of 1.41 (p=0.02).tdEVS were present in 90% of cases (median 7, range 0-1752)at T0 and in 94% at T1 (median 5, range 0-1975). Cox regression showed a significant correlation with survival of tdEVs at T0 (HR=1.0, p=0.004) and T1 (HR=1.0, p=0.009) and the change in tdEVs counts between T0 and T1 (HR=1.01, p=0.04)

Conclusion: CTC and tdEV decrease in the first weeks of immunotherapy was associated with tumor response, whereas an increase in CTC was associated with no response to immunotherapy, indicating a possible use as an early marker.

Citation Format: Menno Tamminga, Sanne de Wit, Joost F. Swennenhuis, T. Jeroen N. Hiltermann, Ed M. Schuuring, Leon W.M. Terstappen, Harry J. Groen. Circulating tumor cells and tumor-derived extracellular vesicles as a possible marker for tumor response and survival in patients with non-small cell lung cancer treated with immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3606.